PFT may be useful for identifying especially high-risk patients with HPR on clopidogrel, for whom treatment escalation needs to be strongly considered. Elderly patients with ACS carry a specific risk profile for both bleeding and ischemic complications. The ANTARCTIC (Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome) trial focused on elderly high-risk ACS patients 75 and older (N=877) to address some limitations of prior studies. 2
The trial compared a reduced prasugrel dose (5 mg/d, per recommendations for elderly patients) with PFT-guided de-escalation (75 mg clopidogrel) or escalation (10 mg prasugrel), and the results found similar rates of ischemic and bleeding in both groups. Low-dose prasugrel superiority over standard treatment with clopidogrel has never been demonstrated, with or without inclusion of PFT.
In clinical practice, it is common to de-escalate P2Y12 inhibiting therapy (ie, from ticagrelor or prasugrel to clopidogrel) in patients with ACS for reasons such as bleeding or bleeding concerns, other adverse effects, and socio-economic factors. However, the potential of increased ischemic risk with uniform de-escalation of P2Y12 inhibiting therapy after PCI should be noted, especially when it is performed too soon post-index event. Dedicated large-scale trials are needed to resolve the conflicting data on uniform de-escalation.
No large-scale trial to date has evaluated efficacy and safety of a routine, unguided de-escalation strategy in high-risk patients with ACS. PFT may prove useful for guiding early de-escalation in this population due to the large-response variability seen with clopidogrel.
The randomized TROPICAL-ACS (Testing responsiveness to platelet inhibition on chronic antiplatelet treatment for acute coronary syndromes (TROPICAL-ACS) trial recently demonstrated net clinical benefit noninferiority in patients scheduled for de-escalation guided by PFT compared with conventional treatment with prasugrel, with similar rates of ischemic events in the guided de-escalation group compared with the control group (32 events vs 42 events; hazard ratio HR 0.77; 95% CI, 0.48-1.21), with a trend towards less bleeding during PFT-guided treatment. 3
A subsequent subgroup analysis showed younger patients deriving a significant net clinical benefit, and further analysis found evidence that PFTR-guided selection of clopidogrel or prasugrel had similar ischemic outcomes compared with uniform therapy with prasugrel in patients without HPR.4
This expert group supports the recent guideline updates based on the results of TROPICAL-ACS, that this strategy be considered as an alternative to 12-month potent platelet inhibition (according to clinician’s judgment) in selected ACS patients (NSTEMI and STEMI). For most (but not all) patients, this guided de-escalation strategy leads to treatment with clopidogrel. The study was limited by being powered to demonstrate net clinical benefit non-inferiority and not ischemic events alone.
Further large-scale trials are needed to corroborate safety with respect to ischemic risks in ACS patients post de-escalation.
General aspects of genotyping & PCI
Common genetic variants for the encoding of cytochromes responsible for active metabolite generation with clopidogrel influence the drug’s antiplatelet action. The utility of genotyping may be disease-specific for this drug, considering consistent strong associations for CAD patients undergoing PCI but not ACS patients who are medically managed or patients with atrial fibrillation.
Data supporting genotyping in patients treated with prasugrel or ticagrelor is lacking given the properties of in-vivo bioactivation and the results of studies regarding the pharmacokinetics/pharmacodynamics (PK/PD) of the potent P2Y12 receptor inhibitors.
As with PFT, a number of different methods and assays are available for genotyping. The expert group recommends using validated rapid assays like the Spartan RX CYP2C19 System over laboratory-based assays (e.g. TaqMan) if timely results are needed. In regard to genotyping targets, research has focused on common polymorphisms within the cytochrome P450 (CYP) 2C19 gene; most importantly, the _CYP2C192 LoF polymorphism that results in a loss of CYP2C19 enzyme activity. Strong, consistent associations have been seen for CYP2C19 LoF (2 and 3) alleles with ischemic events (including stent thrombosis), while data on a possible association with bleeding or ischemic events and CYP2C19_17 is conflicting.
Further summary of genetic variants is beyond the scope of this document, and these variants are only one factor that can affect clopidogrel activity. A number of epigenetic factors are also involved, such as drug interactions and adherence and gastrointestinal absorption, meaning that genotyping cannot be used as a replacement for PFT in assessing antiplatelet drug response.
Genotyping in stable coronary artery disease patients
The available evidence indicates that CYP2C19 genotypes can be used to predict outcomes in clopidogrel-treated patients after elective PCI, with the _CYP2C19_2 and __3 alleles being relevant for ischemic risk prediction and the _17 allele being associated with a higher bleeding risk. Data on using genotyping results for escalating P2Y12 inhibiting therapy in CYP2C19_2 allele carriers (heterozygous or homozygous) is lacking from large, randomized trials. Smaller trials and non-randomized studies have provided some support for genotyping, however.
Consensus advice based on available evidence is that CYP2C19 genotyping (for LoF alleles) may reasonable in specific high-risk scenarios such as left main stenting, last patent vessel PCI, complex lesions, 2-stent bifurcation treatment, and prior stent thrombosis, but should not be used routinely for patients with stable CAD. Furthermore, expert opinion agrees that genotyping may also be used selectively in P2Y12 receptor inhibitor naïve patients who are scheduled for PCI, while genotyping is not recommended to screen for LoF alleles for possible P2Y12 inhibitor de-escalation.
Genotyping in acute coronary syndrome patients
CYP2C19 genotypes (especially LoF alleles) can be used to predict risk in clopidogrel-treated patients after PCI for ACS. Although significant interactions between the CYP2C19 genotype and increased benefits with prasugrel vs clopidogrel were seen in the randomized TRITON-TIMI 38 trial, there is no evidence for using genotyping to guide P2Y12 inhibitor treatment in ACS patients.5
Summary and perspectives
The consensus concluded that “the results of these tests should never be used alone but must be integrated with numerous other clinical, angiographic, procedural and socio-economic variables, which together should guide optimal DAPT decisions. Ultimately, it needs to be acknowledged that different health care systems across the globe may have an impact on the uptake and adherence to different P2Y12 inhibitors as well as reimbursement for PFT or genetic testing.
The experience accumulated over the past decade on studies of PFT and genetic testing to guide the choice of antiplatelet therapy has allowed fine-tuning the design of ongoing clinical trials. Past and ongoing trials in this field are mainly investigator-initiated strategy trials (phase 4IV), which – by definition – differ in many ways from the pivotal phase 3III drug-trials.
Indeed, the results of these ongoing strategy trials that should focus on various areas of clinical use (DAPT escalation, DAPT de-escalation, timing of surgery) will further refine the field of personalizing P2Y12 receptor inhibitor treatment in patients undergoing PCI.”
Disclosure: Multiple authors disclosed affiliations with pharmaceutical companies. See the reference for complete disclosure information.
1. Sibbing D, Angiolillo D, Aradi D, Alexopoulos D, et al. Updated expert consensus statement on platelet function and /genetic testing for guiding P2Y12 receptor -inhibitor treatment in percutaneous coronary intervention [published online June 12, 2019]. JACC Cardiovasc Interv. doi:10.1016/j.jcin.2019.03.034
2. Cayla G, Cuisset T, Silvain J et al. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial [published online August 28, 2016]. Lancet. doi: 10.1016/S0140-6736(16)31323-X
3. Sibbing D, Gross L, Trenk D et al. Age and outcomes following guided de-escalation of antiplatelet treatment in acute coronary syndrome patients undergoing percutaneous coronary intervention: results from the randomized TROPICAL-ACS trial. Eur Heart J. 2018 Aug 1;39(29):2749-2758.
4. Mega JL, Close SL, Wiviott SD et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITONTIMI38 trial: a pharmacogenetic analysis. Lancet. 2010;376:1312-9.